![]() By comparison, briciclib and ON 013100 were relatively non-toxic to normal endothelial cells. ![]() Results: Briciclib and ON 013100 inhibited the proliferation of MCL (JEKO-1 and MINO), breast (MCF7 and MDA-MB-231), gastric (AGS), and esophageal (OE19, OE33, and FLO-1) cancer cell lines at nanomolar concentrations (Briciclib: GI50 = 9.8 - 12.2 nM ON 013100 GI50 = 6.7 - 11.2 nM). Methods: MTT cell viability assays, Western blot analysis, and ELISA assays were used to evaluate cellular viability, survival, and protein expression levels. In addition, we investigated the effect of briciclib and ON 013100 on expression of markers associated with eIF4E activity (cyclin D1 and c-Myc) and apoptosis (P53 and Cleaved Caspase 3). We determined the susceptibility of various breast, mantle cell leukemia (MCL), gastric, and esophageal cancer cell lines to treatment with briciclib or ON 013100. In this study we investigated and compared the anticancer activity of briciclib to ON 013100. Recent advancements in formulation technology have made feasible a stable, orally bioavailable version of ON 013100, which may allow for more convenient administration. An intravenous formulation of briciclib is currently being investigated in a Phase 1 clinical trial. Briciclib is a small molecule, water soluble derivative of ON 013100 that binds to eIF4E. Overexpression of eIF4E has been observed in almost all major groups of cancers and has been shown to induce increased expression of cyclin D1 and c-Myc. eIF4E is a proto-oncogene that promotes translation of several genes essential for cellular proliferation (cyclin D1, c-Myc, mTOR), survival (Akt, survivin), angiogenesis (VEGF), and metastasis (MMP9). Considerations for operationalizing NPK are also summarized.Įnoxaparin generic drug prices levothyroxine mometasone furoate new prior knowledge.Introduction: Eukaryotic translation initiation factor 4E (eIF4E) is a master regulator that controls translation of mRNA in mammalian cells. The paradoxical combination of "new" and "prior knowledge" is chosen deliberately to highlight both a distinction from proprietary and trade secret information and to acknowledge certain historical dogmas inherent in the current practices. The proposed NPK seeks to generate knowledge about critical aspects of pharmaceutical quality and failure modes to place it in the public domain and to facilitate accelerated and more confident development and regulatory review of generic products. The corporate economic advantages of such knowledge are derived, in part, when significant portions remain a trade secret. This knowledge is described as New Prior Knowledge (NPK) because research is often needed to fill ontological (i.e., the domain of connectivity between concepts and phenomena), epistemological (i.e., distinguishing knowledge or justified belief from the opinion), and methodological gaps in information derived a decade or so ago. ![]() This paper focuses on facilitating the utility of prior pharmaceutical formulation knowledge to accelerate drug product development and regulatory review of generic and biosimilar products. Facilitating utility of prior "Chemistry, Manufacturing, and Controls" (CMC) knowledge to accelerate new drug development and regulatory review process is also a topic of significant interest. ![]() For example, progress has been made via modeling and simulation of pharmacokinetic and pharmacodynamic relationships in the more effective use of "End of Phase 2" regulatory meetings for a New Drug Application (NDA). Facilitating utility of prior knowledge to accelerate evidence-based new drug development is a focus of several communities of knowledge, such as clinical pharmacology.
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